Stability Testing Question & Answers –If one of the three submission batches failed at accelerated condition, is it necessary to initiate intermediate study

If one of the three submission batches failed at accelerated condition, is it necessary to initiating intermediate study?

1.According to “USFDA Guidance for industry ANDAs: Stability Testing of Drug Substances and Products - Questions and Answers” If accelerated data show a significant change or failure of any attribute in one or more batches, an applicant should submit intermediate data for all three batches. In addition, the submission should contain a failure analysis (i.e., discussion concerning the observed failure(s)).

Stability Testing Question & Answers; In-use Testing Requirements

How many batches shall be subjected for In-use stability testing during stability study?

1.According to EMA Guidance “Note for Guidance on In-use Stability Testing of Human Medicinal Products” “A minimum of two batches, at least pilot scale batches, should be subjected to the test. At least one of the batches should be chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies”. “If the product is to be supplied in more than one container size or in different strengths, the in-use stability test should be applied to the product which presents the greatest susceptibility to change. The choice of the tested product should always be justified”. 2.According to USFDA Guidance “ANDA Submissions — Content and Format Guidance for Industry” “One-time in-use stability studies for oral liquids and other dosage forms (e.g., a solution to be used within a certain period of opening the container per labeling instructions, compatibility with a dropper when provided as part of the container closure system), as applicable”.

Stability Testing Question & Answers –Antimicrobial Effectiveness Testing (AET) Requirements

The antimicrobial effectiveness test (previously known as the preservative effectiveness test),is a compendial test (antimicrobial test is described in USP <51>) performed during formulation development and stability testing of sterile parenteral multi-dose presentations of drug products that contain a preservative system.This test is intended to reproducible biological measurement of the activity of the preservative system in a product.  

The compendial AET tests of the USP and the European Pharmacopeia have very similar methods, but they differ in sampling points and acceptance criteria. 

How many batches shall be subjected for AET testing during stability study?

1.According to “USFDA Guidance for industry ANDAs: Stability Testing of Drug Substances and Products - Questions and Answers” "One of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed shelf life. The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies".

Stability Testing Question & Answers –Container orientation

What is the recommended container orientatation of stability samples (liquids, solutions,semi solids and suspensions) for US market ?

There are two USFDA guidance’s, which gives inputs on container orientations during stability study. 1.According to USFDA Guidance “ANDA Submissions — Content and Format Guidance for Industry” "For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into worst-case and non-worst-case scenarios. For post-approval stability studies, the applicant should pick the worst-case orientation for the study". 2.According to “USFDA Guidance for industry ANDAs: Stability Testing of Drug Substances and Products - Questions and Answers” "For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into an inverted (or horizontal) position and an upright (or vertical) position. For routine stability studies, the applicant should pick the worst case orientation for the study".